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Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

ABSTRACT: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.

SUBMITTER: Nguyen CT

PROVIDER: S-EPMC6401348 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

Nguyen Cuong Thach CT Bloch Yehudi Y Składanowska Katarzyna K Savvides Savvas N SN Adamopoulos Iannis E IE

Clinical immunology (Orlando, Fla.) 20180906

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. ...[more]

PMID: 30196070

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The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis.

Project description:Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.

| S-EPMC7871349 | biostudies-literature

Mini Review: New Treatments in Psoriatic Arthritis. Focus on the IL-23/17 Axis.

Project description:Psoriasis, an inflammatory skin disease, and psoriatic arthritis (PsA), an inflammatory arthritis, share clinical, genetic, and pathogenic factors and may be summed as one disease, the psoriatic disease. Interleukin (IL)-17 plays a major role in the development of both psoriasis and PsA. IL-23 is important in the proliferation and maintenance of IL-17, and therefore, cytokines of the IL-23/IL-17 axis attracted much interest as therapeutic targets in psoriasis and PsA. Therapeutic agents targeting the IL-23/IL-17 axis have been proven to be very effective in psoriasis and PsA, some are already in the therapeutic armamentarium and others are in the development. Some agents, target IL-23 and others IL-17 and include anti-IL-12/IL-23 p40 (ustekinumab, briankizumab), anti-IL-23p19 (guselkumab, tildrakizumab, risankizumab, brazikumab, mirikizumab), anti-IL-17A (secukinumab, ixekizumab), dual anti-IL-17A and anti-IL-17F (bimekizumab), or anti-IL-17 receptor (brodalumab) monoclonal antibodies. Janus tyrosine kinase(JAK) inhibitors also directly affect IL-23 and, thus, IL-17. After the first-generation pan-JAK inhibitors have been shown efficacy (tofacitinib, baricitinib), new-generation selective JAK inhibitors (filgotinib, upadacitinib) are under investigation in psoriasis and PsA.

| S-EPMC6691125 | biostudies-literature

Human NCF1<sup>90H</sup> Variant Promotes IL-23/IL-17-Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis.

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| S-EPMC10376330 | biostudies-literature

Targeting IL-17 in psoriatic arthritis.

Project description:Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis intimately associated with psoriasis, and can be an impairing disease that leads to reduced quality of life and significant morbidity. Treatment often requires TNF antagonists, yet many patients with PsA are not responsive to the standard anti-TNF therapies. The interleukin-17 (IL-17)/IL-17 receptor (IL-17R) family has recently been implicated in the pathogenesis of PsA and psoriasis. Much enthusiasm has been generated for the development of biologics that target the IL-17 signaling pathway directly or indirectly, many of which have produced striking results in the setting of psoriasis and PsA. Herein, we review the role of IL-17 and the IL-17 receptor (IL-17R) in the pathogenesis of PsA, as well as the clinical evidence for IL-17 and IL-17R targeted therapeutics.

| S-EPMC5741341 | biostudies-literature

Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review.

Project description:Psoriasis is a common inflammatory skin disease with multiple comorbidities, including psoriatic arthritis and coronary artery disease, that can severely impact an individual's quality of life and daily functioning. In recent years, enhanced understanding of the pathogenesis of psoriasis, especially the role of T helper 17 cells, has resulted in the development of new classes of biologic drugs targeting modulators along its disease pathway. Among these, inhibitors of interleukin-23 (e.g., ustekinumab, guselkumab, tildrakizumab, and risankizumab) have emerged as safe and effective options for the treatment of moderate-to-severe plaque psoriasis; ustekinumab and guselkumab have additionally been approved to treat psoriatic arthritis. Selective interleukin-23 inhibitors require less frequent dosing than interleukin-17 inhibitors and may possess a more favorable risk profile without an increased risk of candidiasis or inflammatory bowel disease. Overall, these highly effective medications are contributing to a rising standard for psoriasis outcomes through resolution of skin lesions and joint manifestations and improvement of patient quality of life.

| S-EPMC7727454 | biostudies-literature

Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.

Project description:Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) was able to induce systemic antitumor immunity. Here, we examined the role of IL-23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL-23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL-23-treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL-17-producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti-IL-17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL-23-treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.-Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.

| S-EPMC6662986 | biostudies-literature

Serum IL-23 significantly decreased in obese patients with psoriatic arthritis six months after a structured weight loss intervention.

Project description:IntroductionPatients with psoriatic arthritis (PsA) are frequently obese. We have previously shown decreased disease activity in patients with PsA with a body mass index (BMI) ≥ 33 kg/m2 following weight loss treatment with Very Low Energy Diet (VLED), resulting in a median weight loss of 18.6% at six months (M6) after baseline (BL). In this study we assessed the effects of VLED on cytokines and adipokines at M6 in the same patients with PsA and controls (matched on sex, age and weight).MethodsVLED (640 kcal/day) during 12 or 16 weeks, depending on BL BMI < 40 or ≥ 40 kg/m2, was taken and followed by an energy-restricted diet. Cytokines and adipokines were measured with Magnetic Luminex Assays at BL and M6.ResultsSerum interleukin (IL)-23, (median (interquartile range) 0.40 (0.17-0.54) ng/mL vs. 0.18 (0.10-0.30) ng/mL, p < 0.001) and leptin (26.28 (14.35-48.73) ng/mL vs. 9.25 (4.40-16.24) ng/mL, p < 0.001) was significantly decreased in patients with PsA. Serum total (tot)-adiponectin and high molecular weight (HMW) adiponectin increased significantly. Similar findings were found in controls. Also, in patients with PsA, ∆BMI was positively correlated with ∆IL-23 (rS = 0.671, p < 0.001). In addition, significant positive correlations were found between ΔBMI and ΔDisease Activity Score (DAS28CRP), ΔCRP, Δtumor necrosis factor (TNF)-α, ΔIL-13, ∆IL-17 and Δleptin, and negative correlations between ΔBMI and Δtot-adiponectin.ConclusionsWeight loss was associated with decreased levels of leptin and cytokines, in particular IL-23. These findings may partly explain the anti-inflammatory effect of weight reduction in PsA.Trial registrationClinicalTrials.gov identifier: NCT02917434, registered on September 21, 2016, retrospectively registered.

| S-EPMC10373368 | biostudies-literature

Role of the IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis: The Clinical Importance of Its Divergence in Skin and Joints.

Project description:Psoriasis is a chronic systemic inflammatory disease causing erythematosus and scaly skin plaques; up to 30% of patients with psoriasis develop Psoriatic Arthritis (PsA), which is characterised by inflammation and progressive damage of the peripheral joints and/or the spine and/or the entheses. The pathogenic mechanisms driving the skin disorder in psoriasis and the joint disease in PsA are sustained by the activation of inflammatory pathways that can be overlapping, but also, at least partially, distinct. Cytokines members of the IL-23/IL-17 family, critical in the development of autoimmunity, are abundantly expressed within the cutaneous lesions but also seem to be involved in chronic inflammation and damage of the synovium though, as it will be here discussed, not in all patients. In this review, we will focus on the state of the art of the molecular features of psoriatic skin and joints, focusing on the specific role of the IL-23/IL-17 pathway in each of these anatomical districts. We will then offer an overview of the approved and in-development biologics targeting this axis, emphasising how the availability of the "target" in the diseased tissues could provide a plausible explanation for the heterogeneous clinical efficacy of these drugs, thus opening future perspective of personalised therapies.

| S-EPMC5855752 | biostudies-literature

The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome.

Project description:Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

| S-EPMC8047476 | biostudies-literature

Efficacy and safety of IL-23 inhibitors in the treatment of psoriatic arthritis: a meta-analysis based on randomized controlled trials.

Project description:In recent years, the use of interleukin (IL) 23 inhibitors in the treatment of psoriatic arthritis (PsA) has been the subject of much research. By specifically binding to the p19 subunit of IL-23, IL-23 inhibitors block downstream signaling pathways and inhibit inflammatory responses. The objective of this study was to assess the clinical efficacy and safety of IL-23 inhibitors in the treatment of PsA. PubMed, Web of Science, Cochrane Library, and EMBASE databases were searched from the time of conception to June 2022 for randomized controlled trials (RCTs) investigating the use of IL-23 in PsA therapy. The main outcome of interest was the American College of Rheumatology 20 (ACR20) response rate at week 24. We included six RCTs (3 studies on guselkumab, 2 on risankizumab, and 1 on tildrakizumab) with a total of 2971 PsA patients in our meta-analysis. We found that the IL-23 inhibitor group showed a significantly higher ACR20 response rate compared to the placebo group (relative risk = 1.74, 95% confidence interval: 1.57-1.92; P < 0.001; I2 = 40%). There was no statistical difference in the risk of adverse events (P = 0.07) and serious adverse events (P = 0.20) between the IL-23 inhibitor and placebo groups. Notably, the rate of elevated transaminases in the IL-23 inhibitor group was higher than the placebo group (relative risk = 1.69; 95%CI 1.29-2.23; P < 0.001; I2 = 24%). In the treatment of PsA, IL-23 inhibitors significantly outperform placebo intervention while maintaining a favorable safety profile.

| S-EPMC10425519 | biostudies-literature

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